SCD is an inherited and chronic condition caused by a specific point mutation in a gene that codes for the beta chain of hemoglobin. It affects nearly 100,000 people in the United States and resulting in 3,500 deaths each year. According to Centers for Disease Control and Prevention (CDC), roughly 1 of every 365 black or African American is born with this disease, yet nearly every ethnic population can be affected, including those of Hispanic, South Asian, Southern European and Middle Eastern descent. SCD is also marked by high utilization of medical resources and requires life-long comprehensive care, including emergency treatment and systematic inpatient/outpatient care. Although SCD is a rare disease, it imposes a significant economic burden. The total health care cost exceeds $1 billion in the United States alone with 70,000 to 80,000 hospitalizations each year. In addition, as more people immigrate from endemic regions (e.g. south America, sub-Saharan Africa, Mediterranean countries), SCD will continue to be an important health concern for the United States. Bone marrow (allogeneic hematopoietic stem cell, HSC) transplant is the only treatment available today that potentially cures SCD, however application of this modality is greatly restricted by its high cost, tolerance, and suitable matched donors, for instance, in the United States, only < 14% of patients have a matched sibling donor. Owing to the recent advances in genome modification technologies, the emergence of cutting-edge gene-edited cell therapies, which involve permanent delivery of a corrective or anti-sickling gene cassette into autologous HSCs of patients, could be one-time treatments to overcome the limitation in available donors, immunological side effects, and short-term morbidity and mortality risks associated with bone marrow transplantation. As a result, it is generally considered gene therapies as a new class of transformative medicine to shift treatment of SCD from a chronic disease management toward disease interception and prevention. Functional Fluidics has developed novel microfluidic flow-based cell adhesion assays using a commercial BioFlux 1000Z system (Fluxion Biosciences, San Francisco, CA). These assays are capable of in-vitro assessing pathological interactions of blood cells with vascular endothelium during physiological flow conditions, and Red Blood Cell mechanical fragility (RBC MF) technology, which can evaluate the susceptibility of blood cell hemolysis under applied stresses. Microfluidic technology has been employed in numerous biomedical applications, such as platelet function, coagulation biology, cell-based assays, pharmacology, cardiovascular disease diagnostics, etc. Because microfluidic platforms can mimic the in-vivo conditions found in postcapillary venules, such as dimensions, configuration, shear stresses, temperature, and pulsatility of flow, etc., they become particularly useful for studying microvascular occlusion, the main cause for SCD-associated morbidity and mortality. Their high physiological relevance makes them ideal for discovery of new biomarkers and endpoints to facilitate the development of new SCD therapies. Over the past 5 years, Functional Fluidics has been continuously working with industry and academic partners, including Pfizer, Biogen, Gilead, Agios, Modus Therapeutics, Hemanext, Emmaus Life Science, Novartis, and Detroit Medical Center (DMC), to assess the responses of SCD-modifying therapies using cell adhesion and RBC MF as surrogate endpoints, ranging from observational and pre-clinical studies to early phase clinical trials. Through these collaborations, we have acquired the largest database of sickle erythrocyte functions using our clinical platforms. Moreover, our laboratory is CLIA-certified to provide clinical results for monitoring and assessing RBC function and health in sickle cell patients. We started offering cell adhesion and RBC MF as send-out laboratory developed tests (LDTs) and launched a pilot site at DMC in 2018. Presently, we are negotiating with Children?s National, Promedica, Greenville Health System, Children?s Hospital of Philadelphia, Virginia Commonwealth University, and University of Connecticut Hospitals, and have begun the process of setting up our lab as a vendor. In short, we believe that our novel technologies and profound experience in pharmaceutical and clinical research well-prepare us for this proposed study as described below.